A number of catalytic systems can oxidize sp3-hybridized C—H bonds in R—H to alcohols, R—OH. In particular, tertiary C—H bonds may be selectively oxidized to alcohols, R—OH, because the oxidized carbon in the product is stable against further oxidation. However, attempted hydroxylations of secondary C—H bonds in R—CH2—R′ often result in the formation of the corresponding ketone, R—C(O)—R′, due to the greater ease of oxidation of the immediately resulting secondary alcohol, R—CH(OH)—R′.
Notwithstanding the work on catalytic C—H oxidation to form alcohols, there is little precedent for direct catalytic conversion of R—H to an ether, R—OR′, by reaction with an alcohol, R′OH. Instead, ether formation typically requires an oxidized, pre-functionalized carbon atom in R—X, which has a suitable leaving group X (X=halide, OC(O)R, OSO2R, etc.) that is amenable to a displacement reaction with an alcohol R′OH to give the ether, R—OR′. Moreover, prior art methods typically require installation of the leaving group X on a pre-oxidized species (usually R—OH), and generate waste (base+HX). That said, in a rare example of stoichiometric C—H oxidation directly to form ethers, reaction of 2,4,6-trimethylphenol with stoichiometric CuCl2 and H2O2 in isopropanol and in the presence of a base (K2CO3) gave an ether product. Sun, X. et al. (2008) Catal. Today 131:423-436.